期刊
PLOS ONE
卷 8, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0068669
关键词
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资金
- JST PRESTO program
- Japan Society for the Promotion of Science
- Foundation NAGASE Science Technology Development
- Shorai Foundation for Science and Technology
- Grants-in-Aid for Scientific Research [24659050, 24689007] Funding Source: KAKEN
To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using click chemistry'', by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC(50)s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-kappa B acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors.
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